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Perception (a) and anticipation (b) of severe versus mild dyspnea activated insular, parietal opercular, and cerebellar cortex. (c) Activation during anticipation (displayed in red) and perception of dyspnea (displayed in yellow) overlapped in the left cerebellum and parietal operculum while insular activation was more anterior during anticipation as compared to perception of dyspnea. Activation patterns are displayed at a threshold of p < 0.05 , corrected for the specific ROI, and superimposed on the group-specific T1-weighted mean image generated by the DARTEL-protocol. L = left.
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Dyspnea is common in many cardiorespiratory diseases. Already the anticipation of this aversive symptom elicits fear in many patients resulting in unfavorable health behaviors such as activity avoidance and sedentary lifestyle. This study investigated brain mechanisms underlying these anticipatory processes. We induced dyspnea using resistive-load...
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Citations
... It is no surprise that studies therefore show that distraction during exercise reduces participants effort perception and may allow them to exercise for longer (24,25). However, given the whole course is cycled in VR, our ndings suggest our reductions in perceived exertion may go beyond these well-established effects of analgesia by distraction. ...
... Already, potential neural networks have been theorised to be responsible for these prediction error calculations for breathlessness sensations (25)(26)(27). This Bayesian model of perception seems to be especially compelling within models of pain. ...
Previously we showed that discordant stimulation in virtual reality (VR) could manipulate feelings of breathlessness during stationary cycling. We were interested in developing this as a tool to help respiratory and cardiac patients better engage with exercise rehabilitation. Therefore, in a cohort of healthy volunteers we tested whether the paradigm could attenuate (rather than simply manipulate) feelings of breathlessness and leg fatigue. We explored factors associated with interindividual differences in response. We subsequently investigated clinical acceptability in cardiac and respiratory patients through extensive engagement with relevant stakeholders and a feasibility study. Healthy participants study: 48 healthy people took part in a double-blind, randomised controlled study with two sessions. Participants cycled with a VR headset to compare discordant VR, where visual slope was always less than pedal resistance, against a concordant control. Physical and mental wellbeing were also assessed via questionnaires. Patient and Public Involvement (PPI): The paradigm was demonstrated to 66 patients and caregivers from relevant clinical communities, who then gave feedback in focus groups, panels or one-to-one structured interviews. Patient Study: 9 patients took part in a single session, observational study with a scaled-down version of the cycling paradigm to assess tolerance and acceptability. Healthy participants study: Discordant VR was associated with reduced breathlessness and leg fatigue (breathlessness: effect size estimate = 0.39, SE = 0.04, p<0.00; leg fatigue: effect size estimate = 0.39, SE = 0.04, p<0.001). Further, that depression and health anxiety may influence this effect (breathlessness, Center for Epidemiological Studies Depression score: effect size estimate = 0.29, SE = 0.138, p = 0.04; leg fatigue, Health Anxiety Index: effect size estimate = 0.44, SE = 0.135, p = 0.002). PPI and Patient study: Widespread enthusiasm for concept, identifying a clinical need for novel physical therapy tools. The scaled-down paradigm was mostly well tolerated in a group of relevant patients, with discordant VR approaching significance (effect size: -0.166 , p = 0.06) as a factor in reducing breathlessness, despite small N. Discordant VR has the potential to attenuate breathlessness and effort perception during cycling exercise. This may have clinical utility in cardiac/pulmonary rehabilitation programmes or similar and our findings suggest a formal clinical trial would be merited.
... Importantly, it has long been recognized that the "anticipation" or "expectation" of exercise can increase ventilatory demand and the sensation of dyspnea. (74,75) A recent study by Finnegan et al. used neuroimaging to show that specific brain activity associated with the expectation of dyspnea was correlated with symptom intensity.(76) Further, this could be modulated with Dcycloserine,(76) a brain-active drug potentially influencing the mechanisms underlying "expectations". ...
Purpose of review
Exertional dyspnea and exercise intolerance remain key patient-related outcomes in chronic obstructive pulmonary disease (COPD). Improvement in treatment strategies is pendant further understand of their underpinnings across the spectrum of disease severity.
Recent findings
Emerging literature has been reviewed based on a conceptual framework that relates ventilatory demand to capacity under the modulating influence of sub-cortical and cortical centers (symptom perception and affective interpretation). Evidence supporting these fundamental tenets is critically appraised, focusing on mechanistic and interventional studies that shed novel light on the sources of heightened and/or mechanically constrained ventilation. Mechanistic studies using proxies of the inspiratory neural drive (e.g., diaphragm electromyography) were particularly informative, as well as interventional trials aimed at decreasing afferent stimulation and/or symptom perception via pharmacological (e.g., low-dose opiates in selected patients, high flow oxygen, oral nitrate) and nonpharmacological (e.g., novel exercise training paradigms, inspiratory muscle training, breathing techniques) interventions.
Summary
Therapeutic and rehabilitative strategies to lessen dyspnea's devastating impact on quality of life should minimize demand in the setting of reduced capacity and increased sensation awareness in COPD. The most successful attempts so far have amalgamated pharmacological and nonpharmacological approaches tailored to the main underlying mechanisms on an individual basis.
... Anticipation of dyspnea in patients with COPD may be associated with increased physiological fear responses, activating fear-related areas of the brain such as the insula, anterior cingulate cortex, and amygdala. This reflects anticipatory fear in patients, leading to activity avoidance and further increases in breathlessness [30]. ...
Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by chronic airflow limitation and persistent respiratory symptoms. It is a major cause of morbidity and mortality worldwide, significantly impacting healthcare systems with considerable socioeconomic consequences. The main risk factors include exposure to tobacco smoke, environmental pollutants, occupational dust, and genetic factors such as alpha-1 antitrypsin deficiency. COPD is often associated with extrapulmonary comorbidities, particularly psychiatric disorders like depression and anxiety, which worsen patients’ quality of life and prognosis. The prevalence of these disorders in patients with COPD varies significantly but is always higher than in healthy controls. Psychiatric disorders can negatively influence COPD management and vice versa, creating a complex bidirectional interaction. Depression and anxiety are the most common psychiatric comorbidities in patients with COPD, influenced by factors such as social isolation, physical limitations, and fear of exacerbations. Diagnosis of these psychiatric disorders is complicated by the overlap of symptoms with those of COPD. However, some screening tools can facilitate early detection. The treatment of psychiatric disorders in patients with COPD in a rehabilitation setting requires a multidisciplinary approach involving pulmonologists, neurologists and psychologists. Pharmacological therapy with antidepressants shows mixed results in terms of efficacy and safety, with some studies reporting benefits on quality of life and others suggesting an increased risk of exacerbations and pneumonia. An integrated approach that includes the assessment and intervention of mental disorders is essential to improve the overall management of COPD and the quality of life of patients. This narrative review provides an overview of the main psychiatric comorbidities in COPD patients, aiming to fill gaps in the literature and suggest areas for future research.
... Conventional fMRI studies have reported that effort breathing affects the motor and sensory processes associated with dyspnoea, including the sensory-motor cortex, premotor cortex, SMA, insular cortex, anterior cingulate cortex (ACC), amygdala, thalamus, basal ganglia, cerebellar hemisphere, cerebellar vermis, and brainstem (midbrain, pons, and medulla) regions [2,[16][17][18][19][20][21]. ...
... In this study, we employed whole-brain ROI-to-ROI analysis to screen for changes in FC during mild dyspnoea as well as further examine these changes at the voxel-level using seed-to-voxel analysis. Specially, we aimed to (1) investigate the FC associated with the processing of mild dyspnoea caused by forced breathing; (2) compare the regions identified by conventional fMRI studies [16][17][18][19][20][21]; and (3) explore the relationship between clinical scores. We hypothesised that effort breathing will activate FCs involving previously reported brain regions [16][17][18][19][20][21]. ...
... Specially, we aimed to (1) investigate the FC associated with the processing of mild dyspnoea caused by forced breathing; (2) compare the regions identified by conventional fMRI studies [16][17][18][19][20][21]; and (3) explore the relationship between clinical scores. We hypothesised that effort breathing will activate FCs involving previously reported brain regions [16][17][18][19][20][21]. ...
Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without altering transcutaneous oxygen saturation. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptual area (postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores. These findings may provide new insights into the visual networks that contribute to mild respiratory impairments.
... Conventional fMRI studies have reported that effort breathing activates motor and sensory processes tied to dyspnoea, including the sensory-motor cortex, premotor cortex, SMA, insular cortex, anterior cingulate cortex (ACC), amygdala, thalamus, basal ganglia, cerebellar hemisphere, cerebellar vermis, and brainstem (midbrain, pons, and medulla) regions [16][17][18][19][20][21]. We hypothesised that effortful breathing modulates FC within these brain regions. ...
... We hypothesised that effortful breathing modulates FC within these brain regions. Therefore, in this exploratory study, we aimed to investigate the effects of effort breathing on resting-state connectivity changes and clinical scores (modified Borg scale), focusing on the mentioned brain regions [16][17][18][19][20][21]. ...
... Seeds for first-level seed-to-voxel analysis were selected from the results of our ROI-to-ROI analysis within the regions reported in prior studies [16][17][18][19][20][21] using CONN's default atlas for the definition of ROIs, referred to as the Harvard-Oxford atlas [28][29][30][31]. The mean BOLD time series from these seed regions was extracted and correlated with the time course of each voxel of the brain, resulting in a three-dimensional correlation coefficient (r) map for each subject and seed. ...
Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without changing the saturation of percutaneous oxygen. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptive area of respiration (the postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores.
... 2 Several cortical and subcortical central neural pathways play a role in exacerbating dyspnea in COPD patients. 3 Exertion appears to result in an imbalance between rising central neural drive and impaired thoracic volume displacement. This imbalance intensifies the sensation of dyspnea on exertion. ...
Background:
Dyspnea is frequently a debilitating symptom in chronic obstructive pulmonary disease (COPD). Cannabinoid receptor agonists have potential to alter dyspnea in these patients.
Objective:
To determine if dronabinol, a pure cannabinoid, improves dyspnea and exercise tolerance in COPD.
Methods:
In this double-blind randomized, cross-over pilot study, COPD patients received up to 20mg oral dronabinol or placebo daily for six weeks with an intervening washout period. Dyspnea and fatigue were assessed using Borg scale at rest and after an incremental shuttle walk. Functional status, mood, and depression were measured using St. George's Respiratory Questionnaire (SGRQ), Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ) and Geriatric Depression Scale (GDS).
Results:
Eleven subjects (with mean FEV1 50.8 ± 24.8%) completed the study with no improvement in dyspnea at rest or post exercise taking dronabinol vs. placebo (Borg scale 0.27, 95% CI -0.59 to 1.14 vs. 0.23 points, 95% CI -0.71 to 1.07 at rest and 0.82, 95% CI -0.59 to 2.22 vs. 0.36 points, 95% CI 0.13 to 2.78 post-exercise; p=0.94 and p=0.69 respectively). Dronabinol compared with placebo showed no significant change in PSFDQ dyspnea scores (0.64, 95% CI -3.92 to 5.20 vs. 5.0, 95% CI -6.29 to 16.29; p=0.43) or shuttle walk distances (20.7 m, 95% CI -21.5 to 62.8 vs. 13.7 m, 95% CI -24.8 to 52.2; p=0.69). There were no significant differences in fatigue at rest and post-exercise, SGRQ scores or GDS scores.
Conclusion:
In this pilot study, dronabinol did not significantly improve dyspnea or exercise capacity compared with placebo.
... Breathlessness can occur physiologically, e.g. during exercise, but can also be experienced in many scenarios, including respiratory pathology or psychological distress. Complex interactions between neural networks in the brain are now thought to underpin the perception of breathlessness, and a growing body of research has identified consistent areas of the brain that are associated with breathlessness, including the insula, cingulate and sensory cortices, the amygdala, and the periaqueductal grey matter [5][6][7]. A recent body of research proposes that the perception of breathlessness is influenced by "priors" generated based on expectations learned from past experiences, which determine the importance assigned to sensory inputs [8,9]. ...
... As dyspnea shares similar cortical structures as pain perception (von Leupoldt et al. 2009;Stoeckel et al. 2016), it brings about psychological factors to its origins. The qualitative aspect results in dyspnea being influenced by negative emotions such as fear or anxiety (Smejkal and Charamza 1991), anticipatory cues (Stoeckel et al. 2016), and desensitization protocols (Meek et al. 1999). ...
... As dyspnea shares similar cortical structures as pain perception (von Leupoldt et al. 2009;Stoeckel et al. 2016), it brings about psychological factors to its origins. The qualitative aspect results in dyspnea being influenced by negative emotions such as fear or anxiety (Smejkal and Charamza 1991), anticipatory cues (Stoeckel et al. 2016), and desensitization protocols (Meek et al. 1999). These factors highlight that dyspnea can potentially be manipulated independently of physiology, which it may explain why healthy individuals perceive dyspnea differently than individuals with lung disease and ventilatory limitations. ...
... The assessment of dyspnea perception can be viewed from a psychological perspective, whereby a stimulus is linked to a subjective sensation. Dyspnea activates similar cortical structures involved in pain perception (von Leupoldt et al. 2009), and like pain perception, perceived dyspnea is formed from sensory input, influenced by prior experience (Smejkal and Charamza 1991) and anticipation (Stoeckel et al. 2016). Thus, immediate dyspnea responses can be influenced by one's prior experience and anticipation of dyspnea. ...
The perception of dyspnea is influenced by both physiological and psychological factors. We sought to determine whether exertional dyspnea perception could be experimentally manipulated through prior exposure to heightened dyspnea while exercising. We hypothesized that dyspnea perception during exercise would be lower following an induced dyspnea task (IDT). Sixteen healthy participants (eight females, eight males) completed two days of exercise testing. Day 1 involved an incremental cycle exercise test starting at 40 W for females and 60 W for males, increasing by 20 W each minute until volitional exhaustion. Following the maximal exercise test on Day 1, participants completed IDT, involving 5 min of exercise at 70% of peak work rate with 500 mL dead space and external resistance (i.e., 6.8 ± 2.3 cm·H2O·s⁻¹·L⁻¹ inspiration, 3.8 ± 0.7 cm·H2O·s⁻¹·L⁻¹ expiration). Day 2 consisted of an incremental exercise test identical to Day 1. At maximal exercise, there were no differences in oxygen uptake (V̇O2; 44.7 ± 7.7 vs. 46.5 ± 6.3 mL·kg⁻¹·min⁻¹), minute ventilation (120 ± 35 vs. 127 ± 38 L·min⁻¹), dyspnea (6.5 [4, 8.5] vs. 6 [4.25, 8.75]), or leg discomfort (6 [5, 8.75] vs. 7 [5, 9]) between days (all p > 0.05). At 60%–80% of peak V̇O2 (V̇O2peak), dyspnea was significantly lower on Day 2 (−0.75 [−1.375, 0] for 60% and −0.5 [0, −2] for 80%, p < 0.05) despite no differences in relevant physiological variables. The onset of perceived dyspnea occurred at a significantly higher exercise intensity on Day 2 than on Day 1 (42% ± 19% vs. 51% ± 17% V̇O2peak, respectively; p < 0.05). Except for 40% V̇O2peak (p = 0.05), RPE-L was not different at any intensities nor was the onset of perceived leg discomfort different between days (38% ± 14% vs. 43% ± 10% V̇O2peak, respectively; p = 0.10). Exposure to heightened dyspnea alters exercise-induced dyspnea perception during subsequent submaximal exercise bouts.
... The neuropsychological processes underlying the perception of dyspnea pattern activation observed in the brain areas suggest a possible role for neural deficits in the blunted perception of dyspnea (29). Moreover, dyspnea activates a network of sensorimotor, cerebellar, limbic, and emotion-related areas (30). Exercise with VR systems is often used in neurorehabilitation therapies (patients with multiple sclerosis) and can lead to reduced levels of fatigue (31). ...
Long-post-coronavirus disease-2019 (COVID-19) patients tend to claim residual symptomatology from various systems, most importantly the respiratory and central nervous systems. Breathlessness and brain fog are the main complaints. The pulmonary function pattern is consistent with restrictive defects, which, in most cases, are self-resolved, while the cognitive profile may be impaired. Rehabilitation is an ongoing field for holistic management of long-post-COVID-19 patients. Virtual reality (VR) applications may represent an innovative implementation of rehabilitation. We aimed to investigate the effect of exercise with and without the VR system and to assess further breathlessness and functional fitness indicators in long-post-COVID-19 patients with mild cognitive impairment after self-selected exercise duration using the VR system. Twenty long-post-COVID-19 patients were enrolled in our study (age: 53.9 ± 9.1 years, male: 80%, body mass index: 28.1 ± 3.1 kg/m²). Participants' anthropometric data were recorded, and they underwent pulmonary functional test evaluation as well as sleep quality and cognitive assessment. The participants randomly exercised with and without a VR system (VR vs. no-VR) and, later, self-selected the exercise duration using the VR system. The results showed that exercise with VR resulted in a lower dyspnea score than exercise without VR. In conclusion, VR applications seem to be an attractive and safe tool for implementing rehabilitation. They can enhance performance during exercise and benefit patients with both respiratory and cognitive symptoms.
... Indeed, various neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scanning have been used to visualize brain regions wherein neuronal activity is altered in response to the anticipation and/or perception of laboratory-induced breathlessness (Herigstad et al., 2011). Results from multiple studies in healthy adults (Banzett et al., 2000;Brannan et al., 2001;Evans et al., 2002;Faull and Pattinson, 2017;Liotti et al., 2001;Parsons et al., 2001;Pattinson and Johnson, 2014;Peiffer et al., 2001;Stoeckel et al., 2016von Leupoldt et al., 2008von Leupoldt et al., , 2009 or people with COPD (Esser et al., 2017;Finnegan et al., 2021;Herigstad et al., 2015;Reijnders et al., 2020) indicate that breathlessness is processed in distinct affective and sensorimotor-related brain structures ( Fig. 1) (Banzett et al., 2000;Brannan et al., 2001;Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Parsons et al., 2001;Peiffer et al., 2001;Reijnders et al., 2020;Stoeckel et al., 2016;von Leupoldt and Dahme, 2005;von Leupoldt and Farre, 2020;von Leupoldt et al., 2008von Leupoldt et al., , 2009, most notably and consistently the insular cortex (Banzett et al., 2000;Brannan et al., 2001;Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Peiffer et al., 2001;Stoeckel et al., 2016;von Leupoldt et al., 2008), the anterior cingulate cortex Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Stoeckel, Esser, Gamer, Büchel et al., 2018), and the amygdala Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;von Leupoldt et al., 2008). The anterior cingulate cortex has also been implicated in the relief of breathlessness following a decrease in external resistive loading (Peiffer et al., 2008) or in response to intravenous opioid administration (Pattinson et al., 2009) in healthy people. ...
... Indeed, various neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scanning have been used to visualize brain regions wherein neuronal activity is altered in response to the anticipation and/or perception of laboratory-induced breathlessness (Herigstad et al., 2011). Results from multiple studies in healthy adults (Banzett et al., 2000;Brannan et al., 2001;Evans et al., 2002;Faull and Pattinson, 2017;Liotti et al., 2001;Parsons et al., 2001;Pattinson and Johnson, 2014;Peiffer et al., 2001;Stoeckel et al., 2016von Leupoldt et al., 2008von Leupoldt et al., , 2009 or people with COPD (Esser et al., 2017;Finnegan et al., 2021;Herigstad et al., 2015;Reijnders et al., 2020) indicate that breathlessness is processed in distinct affective and sensorimotor-related brain structures ( Fig. 1) (Banzett et al., 2000;Brannan et al., 2001;Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Parsons et al., 2001;Peiffer et al., 2001;Reijnders et al., 2020;Stoeckel et al., 2016;von Leupoldt and Dahme, 2005;von Leupoldt and Farre, 2020;von Leupoldt et al., 2008von Leupoldt et al., , 2009, most notably and consistently the insular cortex (Banzett et al., 2000;Brannan et al., 2001;Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Peiffer et al., 2001;Stoeckel et al., 2016;von Leupoldt et al., 2008), the anterior cingulate cortex Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Stoeckel, Esser, Gamer, Büchel et al., 2018), and the amygdala Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;von Leupoldt et al., 2008). The anterior cingulate cortex has also been implicated in the relief of breathlessness following a decrease in external resistive loading (Peiffer et al., 2008) or in response to intravenous opioid administration (Pattinson et al., 2009) in healthy people. ...
... Indeed, various neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scanning have been used to visualize brain regions wherein neuronal activity is altered in response to the anticipation and/or perception of laboratory-induced breathlessness (Herigstad et al., 2011). Results from multiple studies in healthy adults (Banzett et al., 2000;Brannan et al., 2001;Evans et al., 2002;Faull and Pattinson, 2017;Liotti et al., 2001;Parsons et al., 2001;Pattinson and Johnson, 2014;Peiffer et al., 2001;Stoeckel et al., 2016von Leupoldt et al., 2008von Leupoldt et al., , 2009 or people with COPD (Esser et al., 2017;Finnegan et al., 2021;Herigstad et al., 2015;Reijnders et al., 2020) indicate that breathlessness is processed in distinct affective and sensorimotor-related brain structures ( Fig. 1) (Banzett et al., 2000;Brannan et al., 2001;Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Parsons et al., 2001;Peiffer et al., 2001;Reijnders et al., 2020;Stoeckel et al., 2016;von Leupoldt and Dahme, 2005;von Leupoldt and Farre, 2020;von Leupoldt et al., 2008von Leupoldt et al., , 2009, most notably and consistently the insular cortex (Banzett et al., 2000;Brannan et al., 2001;Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Peiffer et al., 2001;Stoeckel et al., 2016;von Leupoldt et al., 2008), the anterior cingulate cortex Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;Stoeckel, Esser, Gamer, Büchel et al., 2018), and the amygdala Esser et al., 2017;Evans et al., 2002;Herigstad et al., 2011;Liotti et al., 2001;Marlow et al., 2019;von Leupoldt et al., 2008). The anterior cingulate cortex has also been implicated in the relief of breathlessness following a decrease in external resistive loading (Peiffer et al., 2008) or in response to intravenous opioid administration (Pattinson et al., 2009) in healthy people. ...
Breathlessness is a centrally processed symptom, as evidenced by activation of distinct brain regions such as the insular cortex and amygdala, during the anticipation and/or perception of breathlessness. Inhaled L-menthol or blowing cool air to the face/nose, both selective trigeminal nerve (TGN) stimulants, relieve breathlessness without concurrent improvements in physiological outcomes (e.g., breathing pattern), suggesting a possible but hitherto unexplored central mechanism of action. Four databases were searched to identify published reports supporting a link between TGN stimulation and activation of brain regions involved in the anticipation and/or perception of breathlessness. The collective results of the 29 studies demonstrated that TGN stimulation activated 12 brain regions widely implicated in the anticipation and/or perception of breathlessness, including the insular cortex and amygdala. Inhaled L-menthol or cool air to the face activated 75% and 33% of these 12 brain regions, respectively. Our findings support the hypothesis that TGN stimulation contributes to breathlessness relief by altering the activity of brain regions involved in its central neural processing.
